title: Incremental benefits of repeated mesenchymal stromal cell administration compared with solitary intervention after myocardial infarction.
abstract: OBJECTIVE
  Traditionally, stem cell therapy for myocardial infarction (MI) has been administered as a single treatment in the acute or subacute period after MI. These time intervals coincide with marked differences in the post-infarct myocardial environment, raising the prospect that repeat cell dosing could provide incremental benefit beyond a solitary intervention. This prospect was evaluated with the use of mesenchymal stromal cells (MSCs).
  
  
  METHODS
  Three groups of rats were studied. Single-therapy and dual-therapy groups received allogeneic, prospectively isolated MSCs (1 × 10(6) cells) by trans-epicardial injection immediately after MI, with additional dosing 1 week later in the dual-therapy cohort. Control animals received cryopreservant solution only. Left ventricular (LV) dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance immediately before MI and at 1, 2 and 4 weeks after MI.
  
  
  RESULTS
  Immediate MSC treatment attenuated early myocardial damage with EF of 35.3 ± 3.1% (dual group, n = 12) and 35.2 ± 2.2% (single group, n = 15) at 1 week after MI compared with 22.1 ± 1.9% in controls (n = 17, P < 0.01). In animals receiving a second dose of MSCs, EF increased to 40.7 ± 3.1% by week 4, which was significantly higher than in the single-therapy group (EF 35.9 ± 1.8%, P < 0.05). Dual MSC treatment was also associated with greater myocardial mass and arteriolar density, with trends toward reduced myocardial fibrosis. These incremental benefits were especially observed in remote (non-infarct) segments of LV myocardium.
  
  
  CONCLUSIONS
  Repeated stem cell intervention in both the acute and the sub-acute period after MI provides additional improvement in ventricular function beyond solitary cell dosing, largely owing to beneficial changes remote to the area of infarction.
authors.affiliation: Cardiovascular Research Centre, Royal Adelaide Hospital, South Australia, Australia; Department of Medicine, University of Adelaide, South Australia, Australia; Centre for Stem Cell Research, Robinson Institute, School of Medical Sciences, University of Adelaide, South Australia, Australia.
authors.forename: James D
authors.initials: JD
authors.lastname: Richardson
authors.affiliation: Cardiovascular Research Centre, Royal Adelaide Hospital, South Australia, Australia; Department of Medicine, University of Adelaide, South Australia, Australia; Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Psaltis
authors.affiliation: Cardiovascular Research Centre, Royal Adelaide Hospital, South Australia, Australia; Department of Medicine, University of Adelaide, South Australia, Australia.
authors.forename: Lachlan
authors.initials: L
authors.lastname: Frost
authors.affiliation: Centre for Stem Cell Research, Robinson Institute, School of Medical Sciences, University of Adelaide, South Australia, Australia.
authors.forename: Sharon
authors.initials: S
authors.lastname: Paton
authors.affiliation: Cardiovascular Research Centre, Royal Adelaide Hospital, South Australia, Australia; Department of Medicine, University of Adelaide, South Australia, Australia.
authors.forename: Angelo
authors.initials: A
authors.lastname: Carbone
authors.affiliation: Cardiovascular Research Centre, Royal Adelaide Hospital, South Australia, Australia; Department of Medicine, University of Adelaide, South Australia, Australia.
authors.forename: Angela G
authors.initials: AG
authors.lastname: Bertaso
authors.affiliation: Cardiovascular Research Centre, Royal Adelaide Hospital, South Australia, Australia; Department of Medicine, University of Adelaide, South Australia, Australia.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Nelson
authors.affiliation: Cardiovascular Research Centre, Royal Adelaide Hospital, South Australia, Australia; Department of Medicine, University of Adelaide, South Australia, Australia.
authors.forename: Dennis T L
authors.initials: DT
authors.lastname: Wong
authors.affiliation: Cardiovascular Research Centre, Royal Adelaide Hospital, South Australia, Australia; Department of Medicine, University of Adelaide, South Australia, Australia.
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Worthley
authors.affiliation: Centre for Stem Cell Research, Robinson Institute, School of Medical Sciences, University of Adelaide, South Australia, Australia.
authors.forename: Stan
authors.initials: S
authors.lastname: Gronthos
authors.affiliation: Centre for Stem Cell Research, Robinson Institute, School of Medical Sciences, University of Adelaide, South Australia, Australia.
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
authors.affiliation: Cardiovascular Research Centre, Royal Adelaide Hospital, South Australia, Australia; Department of Medicine, University of Adelaide, South Australia, Australia; Centre for Stem Cell Research, Robinson Institute, School of Medical Sciences, University of Adelaide, South Australia, Australia. Electronic address: Stephen.Worthley@adelaide.edu.au.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Worthley
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D006801:Humans; D007267:Injections; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D051381:Rats; D013318:Stroke Volume; D016277:Ventricular Function, Left
keywords: cardiac magnetic resonance; hypoxic conditioning; mesenchymal stromal cells; multiple intervention; myocardial infarction; optimization; prospective isolation; repair; timing